Aldol condensation reactions are important in the production of intermediates needed to synthesize many commercially important products. The condensation of ketones to obtain aldols (β-hydroxy ketones) is a well-known reaction. Dehydration of the resulting aldol to obtain an unsaturated ketone is also known. Subsequent catalytic hydrogenation of the unsaturated ketone may be carried out to obtain the corresponding saturated higher ketone.
In an aldol condensation reaction, an aldehyde or ketone, with a hydrogen atom alpha to the carbonyl, react together to form a β-hydroxy-aldehyde or a β-hydroxy-ketone. The β-hydroxy-aldehyde or β-hydroxy-ketone can dehydrate in the presence of either an acid or a base to give a conjugated α,β-unsaturated aldehyde or ketone. The conditions needed for the aldol dehydration are often only slightly more vigorous than the conditions needed for the aldol condensation itself. As a result, the product of such aldol reactions often comprises both the β-hydroxy aldehyde or ketone and the α,β-unsaturated aldehyde or ketone.
Many methods have been disclosed in the art to perform aldol condensation reactions. These include two-phase liquid reactions using dilute aqueous base as the catalyst, see, for example, U.S. Pat. No. 6,232,506, U.S. Pat. Appln. No. 2002/0161264, U.S. Pat. No. 6,433,230, U.S. Pat. No. 2,200,216, U.S. Pat. No. 6,288,288; base-catalyzed, liquid phase aldol condensation reactions that include the use of a solubilizing or phase transfer agent, see, for example, U.S. Pat. Nos. 2,088,015, 2,088,016, 2,088,017, and 2,088,018; and the use of polymeric or oligomeric ethylene glycols or polyhydric alcohols as phase transfer catalysts or solvents in combination with dilute alkali metal hydroxide catalysts, see, for example, U.S. Pat. Nos. 5,055,621, and 5,663,452, and U.S. Pat. Publ. No. 2002/0058846.
Several authors have disclosed processes for crossed aldol condensations catalyzed by relatively high levels of caustic. Weizmann and Garrard, J. Chem. Soc, Pt. 1, Vol. 117, 1920, pp. 324–338, prepared 3-hepten-2-one by the batch-wise crossed condensation of n-butyraldehyde and acetone catalyzed with solid sodium hydroxide. Eccott and Linstead, J. Chem. Soc, Pt. 1, Vol. 133, 1930, pp. 904–911, prepared a mixture of 4-hydroxy-2-heptanone and 3-hepten-2-one by the low-temperature, (5–10° C.) batch-wise crossed condensation of n-butyraldehyde and acetone catalyzed by 50 weight percent sodium hydroxide. As another example, U.S. patent application Ser. No. 10/611,394, filed Jul. 1, 2003 and having common assignee herewith, describes a process for the preparation of β-hydroxy-ketones and/or α,β-unsaturated ketones in unexpectedly high yields by the liquid-phase crossed condensation of an aldehyde with a ketone, in the presence of a small amount of a catalyst comprising a concentrated hydroxide or alkoxide of an alkali-metal or alkali-earth metal, wherein the amount of water present in the reaction mixture is kept relatively low, with respect to the total weight of reactants.
The β-hydroxy-aldehyde or β-hydroxy-ketone product of such aldol condensations can dehydrate to give a conjugated α,β-unsaturated aldehyde or ketone. Many methods are known in the art for dehydrating β-hydroxy-aldehydes or β-hydroxy-ketones to α,β-unsaturated aldehydes or ketones, in fair to excellent yields. These include simple heating; acid-catalyzed dehydration using mineral acids or solid acid catalysts, with or without azeotropic removal of the water of reaction, as exemplified in U.S. Pat. No. 5,583,263, U.S. Pat. No. 5,840,992, U.S. Pat. No. 5,300,654, and Kyrides, JACS, Vol 55, August, 1933, pp. 3431–3435; heating with iodine crystals, as in Powell, JACS, Vol. 46, 1924, pp. 2514–17; and base-catalyzed dehydration, as taught in Streitwieser and Heathcock, “Introduction to Organic Chemistry”, 2nd Ed., 1981, pp. 392–396.
Aldehydes are more reactive, in general, than are ketones in base-catalyzed aldol condensations, because of the greater ease of enolate ion formation of an aldehyde. As such, in a crossed condensation of a ketone with an aldehyde to produce a desired β-hydroxyketone, the self-condensation of the aldehyde typically occurs in substantial quantities to produce an undesired β-hydroxyaldehyde by-product. Further, unhindered aldehydes, i.e., straight-chain aldehydes such as acetaldehyde, propionaldehyde, n-butyraldehyde, and n-pentanal, are more reactive toward self-condensation than are hindered aldehydes, i.e., branched aldehydes such as 2-methyl-propanal and 3-methyl-butanal.
It is understood that the rate-limiting step in these reactions is often the enolate ion formation, and that condensation and the subsequent dehydration reaction occur in rapid succession. These α-β unsaturated ketones and aldehydes are known to those skilled in the art to be quite reactive and susceptible to further consecutive, non-selective condensation, cyclization, and Michael-type addition reactions with the starting ketones and aldehydes, as well as themselves and other ketonic and aldehydic by-products. See, for example, H. O. House, Modern Synthetic Reactions, 2nd. Ed., 1972 pp. 595–599, 629–640.
Thus, without being bound by any theory, in the base-catalyzed condensation of an aldehyde of Formula 1, possessing at least one hydrogen atom alpha to the carbonyl, with a ketone of Formula II, to form a desired β-hydroxy-ketone or α-β unsaturated ketone of Formulae III or IV, three parallel reaction pathways are known to compete:

In general, R2 represents a C1 to C10 organic radical and R1, R3, and R4 represent hydrogen or a C1 to C10 organic radical.
R1 may represent a hydrogen, or else R1 and R2 may form members of a common cycloalkyl or aromatic ring, either of which may be substituted with one or more functional groups, or else R2 represents an alkyl group, which may be straight or branched, and which may be substituted with one or more functional groups;
R3 and R4 each independently represent hydrogen, or else R3 and R4 form members of a common cycloalkyl or aromatic ring, either of which may be substituted with one or more functional groups, or else one or both may represent a branched or unbranched, saturated or unsaturated aliphatic or alkyl-substituted cycloalkyl hydrocarbon radical; or else each represents an aryl hydrocarbon radical, or an alkylaryl hydrocarbon radical, either of which may be substituted with one or more functional groups.
One skilled in the art would expect a broad range of products from these reactions, and difficulty in stopping the reactions at the β-hydroxy-ketone stage. The further condensation of the α-β unsaturated ketones with the ketone of Formula II, or with the aldehyde of Formula I, or with other ketonic and aldehydic species, leads to a plethora of by-products and can represent significant yield losses as well as necessitating complicated and expensive purification schemes for the commercial production of high purity β-hydroxy-ketones and/or α,β-unsaturated ketones. For example, in the preparation of 2-heptanone via the condensation of n-butyraldehyde with acetone, the self-condensation of n-butyraldehyde to form 2-ethyl-2-hexenal is a particularly troublesome by-product. Its hydrogenated form, 2-ethylhexanal, boils less than 10° C. apart from 2-heptanone, and is therefore difficult to separate economically from 2-heptanone by distillation.
One method of preventing unwanted further condensation side products in aldol condensation reactions is to quickly hydrogenate the α,β-unsaturated ketones. This can be accomplished in situ or in a separate hydrogenation step.
In some cases, it is desirable to selectively hydrogenate the carbon—carbon double bond of the resulting α,β-unsaturated ketone to give a saturated ketone. Catalysts and methods are known for such hydrogenation reactions, as exemplified in U.S. Pat. Nos. 5,583,263 and 5,840,992, and U.S. Pat. Appl. Nos., 2002/0128517, 2002/058846, and 2002/0169347. Alkenes react with hydrogen gas in the presence of a suitable metal catalyst, typically palladium or platinum, to yield the corresponding saturated alkane addition products. The metal catalysts are normally employed on a support or inert material, such as carbon or alumina. Commercially important products of this type include methyl amyl ketone, methyl isoamyl ketone, and methyl propyl ketone, made by the crossed condensation of acetone with n-butryaldehyde, isobutyraldehyde, or acetaldehyde, respectively.
The production of higher molecular weight ketones using aldol condensations and catalytic hydrogenations can be carried out either by a multi-step process or a single-step process. A multi-step process uses sequentially discrete steps in two or three separate reactors. In a single-step process the reactions are carried out simultaneously in one reactor.
When ketones are synthesized by a multi-step process, using sequentially discrete steps, the aldol reaction occurs first, which is then followed by dehydration, and by subsequent hydrogenation. Each step is independent of the others, and the process often requires difficult separation techniques between steps. For example, U.S. Pat. No. 5,583,263 describes a multi-step process for the coproduction of methyl amyl ketone and methyl isobutyl ketone. In this process, dimethyl ketone is reacted with n-butyraldehyde using a fixed-bed basic ion exchange cross-aldol condensation catalyst to form a β-hydroxy ketone mixture. The product is then dehydrated to form an olefinic ketone using a catalytic quantity of an acidic substance, such as H2SO4, NaHSO4, or a sulfonic acid resin. The resulting α,β-unsaturated ketone is then hydrogenated using a solid phase hydrogenation catalyst to produce the desired amyl ketone. Three discrete steps are required, with costly separations between the steps. There is no acknowledgment that by-products other than methyl isobutyl ketone are produced, nor is there any suggestion how one might avoid impurities such as 2-ethylhexaldehyde and high boiling by-products that result from unwanted side reactions. On the basis of a comparative example, the authors conclude that commercial coproduction of methyl isobutyl ketone and methyl amyl ketone is impractical in one-step processes employing ordinary catalyst systems.
Another example of a multi-step process is found in U.S. Pat. No. 5,840,992 ('992), which teaches a process for producing 6-methylheptan-2-one by the crossed condensation of acetone with 3-methyl-butanal, in the presence of an aqueous alkali or alkali earth metal hydroxide as catalyst, at a catalyst-aldehyde molar ratio of 0.001 to 0.20. In a separate step, the resulting β-hydroxy ketone condensation product is further subjected to reduction under dehydrating conditions to produce 6-methylheptan-2-one. The process according to the '992 patent may be carried out continuously in plug flow or batch-wise mode. Typical molar selectivities on 3-methyl-butanal are about 75 to 80 percent, with the best results being achieved in the batch mode of operation. Although the '992 patent suggests that the basic catalyst substance may be used as an aqueous solution at a concentration between 1 and 50 percent, the process is reduced to practice only with a catalyst concentration of 5 weight percent aqueous sodium or potassium hydroxide. The authors of the '992 patent clearly fail to contemplate the advantages of using concentrated hydroxides or alkoxides of alkali earth- or alkali-metals as catalysts, for example at greater than 15 or 20 weight percent, while controlling the absolute amount of water present in the reaction mixture. Thus, the process disclosed in the '992 patent achieves only modest yields.
U.S. Pat. No. 6,232,506 discloses a multi-step process for producing 6-methyl-3-heptan-2-one, and its analogues, by the crossed aldol condensation of acetone with 3-methyl-butanal (isovaleraldehyde), in the presence of an aqueous alkali containing an alkaline substance. The 6-methyl-3-hepten-2-one is then separately hydrogenated to 6-methyl-3-heptan-2-one in the presence of a hydrogenation catalyst. The aldol catalyst is provided as a 0.5 to 30 weight percent, preferably 1 to 10 weight percent, aqueous solution, at a caustic-aldehyde molar ratio of 0.001 to 0.2. The process is carried out in semi-batch mode, with separate continuous feeds of aldehyde and dilute caustic to a stirred reaction zone initially comprising acetone. In Example 3 of the patent, using the preferred 2 wt. % aqueous caustic catalyst solution, the reaction mixture forms distinct aqueous and organic phases, with water being present in an amount of about 39 wt. %, based on the total weight of the reactant mixture. 6-methyl-3-hepten-2-one is hydrogenated in the presence a 5% palladium on carbon catalyst for 7 hours. Cited yields are typically about 66% to 6-methyl-3-hepten-2-one and 3.3% 6-methyl-4-hydroxy-heptan-2-one.
U.S. Pat. No. 6,603,047 discloses a step-wise process for the preparation of ketones by the crossed condensation of an aldehyde with a ketone, followed by the hydrogenation of the unsaturated ketone. The condensation reaction described can be carried out in a tubular reactor as a multiphase liquid reaction in which a dilute aqueous caustic catalyst (0.1 to 15 weight percent caustic, preferably 0.1 to 5 weight percent) is the continuous phase and the aldehyde/ketone reactants are the dispersed phase. This patent explains that the reaction must be conducted with separate catalyst and reactant phases, and that the mass ratio of the aqueous caustic phase to the organic reactant phase can be from 2:1 to 10:1, preferably even greater. The reference clearly fails to contemplate the advantages of a high caustic catalyst phase reaction in which the amount of water present is kept relatively low. The patent claims the unsaturated ketone is hydrogenated in a separate step, but this concept is not reduced to practice in the examples.
When ketones are produced in a single-step process, the aldol reaction, dehydration, and hydrogenation occur simultaneously in one reactor. Such single-step processes can be either batch or continous processes.
In a single-step batch process, the reactions are carried out simultaneously in one reactor, and there is neither inflow nor outflow of reactants or products while the reaction is being carried out. In a one-step continuous process, the reactions are carried out simultaneously in one reactor, and reactants flow in and the products flow out while the reaction is being carried out. While the hydrogenation reaction is typically heterogeneously catalyzed, the aldol condenstion can be either heterogeneously or homogeneously catalyzed in a one-step process.
For example, U.S. Pat. No. 2,499,172 (the '172 patent) describes a single-step batch process for the conversion of low-boiling ketones to high boiling ketones. Higher boiling ketones, such as methyl isobutyl ketone, are produced when lower boiling ketones, such as acetone and ethyl methyl ketone, are treated with hydrogen in the presence of a liquid alkaline condensation catalyst and a solid hydrogenation catalyst. The liquid alkaline condensation catalyst can be ammonia; amines, such as isopropylamine, diisopropylamine, trimethylamine, furfurylamine, difurfurylamine, and aniline; alkali-metal hydroxides; alkaline-earth-metal oxides and hydroxides; and alkali-metal salts of weak acids, such as sodium borate, carbonate, acetate and phosphates. The solid hydrogenation catalyst can contain palladium, for example 5% Pd/C.
The examples of the '172 patent describe a single-step batch process for the self-condensation of ketones. In general, self-aldol condensations of ketones lead to only one product. For example, the self-aldol condensation and hydrogenation product of dimethylketone is methyl isobutyl ketone. However, crossed aldol condensations—between ketones and aldehydes—lead to mixtures of products. For example, the crossed aldol condensation and hydrogenaton products of dimethylketone and n-butyraldehyde are methyl amyl ketone, methyl isobutyl ketone, and 2-ethylhexaldehyde. We have found that when the one-step batch process described in the '172 patent is applied to the crossed aldol condensation of acetone and n-butyraldehdye, as seen in Example 1 (Comparative) of the present application, a large amount of high-boiling material is produced. As a result, the selectivity of n-butyraldehyde to methyl amyl ketone is poor. A further disadvantage of batch processes in general is that they often require large reaction vessels and storage tanks, because their productive capacity relative to the reaction volume is very small. Other drawbacks include high energy consumption and high labor requirements.
U.S. Pat. No. 6,583,323 describes a single-step process for the preparation of 6-methylheptan-2-one and corresponding homologous β-branched methylketones, in particular phytone and tetrathydrogeranyl acetone, by the two-liquid phase crossed condensation of acetone with 3-methyl-butanal, prenal or the like, in the presence of both a dilute aqueous alkali or alkali earth metal hydroxide catalyst for the aldol step and a noble metal catalyst for hydrogenation. A base concentration of 0.01 to 20 weight percent in the aqueous catalyst phase is said to be useful, from 0.5 to 5 wt. % being preferred, though the concentration is said not to be critical. The processes exemplified in this document use relatively low concentrations of caustic with a relatively high amount of water, with respect to the total weight of the reactants. The reactivity toward self-condensation of the hindered, branched aldehyde, 3-methyl-butanal, is low, resulting in molar selectivities based on the aldehyde of around 93–95 mole percent.
U.S. Pat. Publ. No. 2002/0058846 teaches a single-step process for the preparation of 6-methylheptan-2-one and corresponding homologous β-branched methylketones, in particular phytone and tetrathydrogeranyl acetone, by the two-liquid phase crossed condensation of acetone with 3-methyl-butanal, prenal or the like, in the presence of a dilute aqueous alkali or alkali earth metal hydroxide catalyst dissolved in a polyhydric alcohol for the aldol step, and a noble metal catalyst for hydrogenation. The polyhydric alcohol is preferably glycerol. This process suffers from low reaction rates and complicated separation schemes for recovery and recycling of the phase transfer catalyst.
U.S. patent application Ser. No. 10/713,727, filed Nov. 14, 2003 and having common assignee herewith, describes a single-step process for producing higher molecular weight ketones, which occurs in a fixed-bed reactor system. Aliphatic ketones or aldehydes are condensed together using a dilute liquid base as an aldol catalyst. The resulting intermediate is dehydrated by the liquid base to yield an unsaturated intermediate. This olefinic species is then hydrogenated over a solid metal catalyst on an inert support. While high conversions and good selectivity are achieved with this process, high recycle rates are suggested for low by-product formation. There remains a need for an improved process for producing higher molecular weight ketones having a higher yield and greater selectivity for the target product, which minimizes the amounts of unwanted by-products that are afterward difficult to remove from the reaction mixture.